PART II

SYNTHESIS OF PYRAZOLINES

CHAPTER -1

INTRODUCTION

Importance of pyrazolines:

Pyrazolines are lound to possess unlidiuretic , anlihelmenlic and fungicidal acliviiy

Pyrazolines are also used as antiinnammaiory agents and very etTective in killing houscllies

on contact-. They are tested for bactericidal and fungicidal activity. Recently sonic N-aceiyl.

N-aryl pyrazoline derivatives are reported as more effective than isoxazolcs and other coun-

.terparts literature survey reveals the importance of pyrazolines as bleaching agents and

luminiscent apart from their use as drugs, [pyrazolines are widely applicable in photography

due to their excellent sensitivity.

Structure of pyrazolines :

A five membered ring containing adjacent nitrogen atoms was termed as pyrazole (A)

by Knorr^ in 1883. The dihydropyrazole is called as pyrazoline (B).

H . H I I

Pyrazole Pyrazoline

(A) (B)

If the nitrogen atom in pyrazoline is substituted, tautomerism is exhibited by the struc-

tures C. D and E. The taulomers C and D are more stable than H and are known as A--

pyrazolines and A^-pyrazolines respectively. No evidence for the stability of tauiomer l" has

64

been reported.

H 1

N 1

H 1

1

H 1

N . N .

(C) (D) (!•:)

Synthesis in pyrazolines:

The most convenient method for the synthesis of pyrazoline is the action ol

phenylhydrazine on a,P-carbonyl compounds. In the above reaction, the intcrmedieate

formed is a hydrazone or phenylhydrazone respectively. This was sub.sequenily cycli.sed to

pyrazoline", in the presence of a suitable cyclizing reagent. «

The most widely used reagent for cyclization of hydrazone is acetic acid\ Alcohol

containing a little HCl also serves this purpose, but gives poor yield. The rate of cyclization

of hydrazane to pyrazoline also depends upon the nature of R'. It is in the order

R'=Ph>Me>H^^

R.NHNH, Cyclization

R'-C-CH=CH-R > R'-C=CH-R > N If II 0 N.NHR- Rl

R-

Benzylidene acetophenone with an excess of hydrazine in boiling acetic acid, gave N-

acetyl-3,5-diphenylpyrazoline which could be immediately convened into 3.5-

diphenylpyrazoline.

C-CH=CH-

Under normal conditions subslilutcd hydrazines and chalcones give hydra/one de-

rivatives. Dhar'̂ and Yaraslawaski'" reported 2,4-dinitrophenyl hydrazone ofchaicone. The

ring closer takes place with the substituted pyrazolines from chalcone and hydrazine deriva-

tives under only vigorous conditions.

Baker etal" have reported the formation of l-phenyl-(2-hydroxy-4-meihoxyphenyl)-

3-methylpyrazoline from 2-hydroxy-4-methoxyslrylmethyI ketone, on treatment with

phenylhydrazine. Gh.eorghiu and Matei'- have attempted to correlate the ease of formation

of pyzazoline with steriomeric forms of phenylhydrazone. The syn-form (also called

nonprototropic) cannot be converted into pyrazoiine. It is known that pyridine' does not

retard the conversion of syn-form to pyrazoiine.

OMe

The presence of an electron donating group such as hydroxyl, alkoxyl and amino or

either of the phenyl rings or benzalacetophenone makes the phenylhydrazone more labile

and it can seldom be isolated*' '̂ •"'. The electron withdrawing groups like nitro and halogen

stabilize the hydrozone'^'"'"-'. Unsymmetrically substituted dibenzalacetone does not yield

an intermediate hydrazone but gives the corresponding pyrazolines directly.

The mechanism of the formation of pyrazoiine was suggested by Aubagnac et al"

from a,P-unsaturaied ketones by 1,2 addition of phenyl hydrazine through an adduct inter-

mediate. The rate determining step is the dehydration of the adduct giving hydrazone which

has been supported from the activation energy calculation'** of l,3.5-tripyra/t)iine. The

66

cyciization of pyrazoline is shown to be spontaneous'^

OH Ph.NH.NH, I

Ph-C-CH=CH-Fh ^ Pli-C-CH=CH-l'h II O NH.NH.Ph

Ph 1

/ N Ph N T H = R'-4 I R,

Sammour" has reported the synthesis of 4-hydroxy substituted pyrazolines from

chalcone epoxide on treatment with substituted hydrazine

67

R ()

R-

% ^ < ^ K '

R-

2'-Hydroxychalcone phenylhydra/.one changes lo llavanone on ireaimeni with alkali

and reverse change is brought about with acetic acid. The themial reaiiangemeni ol navant)ni'

phenylhydrazone to pyrazoline has been shown and the results are consisiant with the se-

quence of events in the chart given below.

OH'

Ĥ

OH

Ph.NH.NH,

N.NHPh

KOH J:̂ .

AcOH

OH

C-->

C-CH=CH II O

It has been also investigated that the reaction of llavanone with hydra/me '*and

phenylhydrazine-*-^ under different experimental conditions , affords the lorniation ol

hydrazone pyrazoline-'*-^ and falavanoneazine -''•-'^~\ The main factors inlluencing the course

of the reaction are pH, temperature and the amount of hydrazine in the reaction mixture.

Here the formation of pyrazoline through an intermediate llavannone hydrazone is not re-

poiied-^

° Y ^

O

(Flavanone azine)

NH.. NH.

N.NH,

(Flavanone hydrazone)

,C)H

«~1 Ph

(Pyrazoline)

Synthesis of 3.5-diaryl-l-phenylpyrazoline was reported by Barkhade and Marathey-"

by the action of Ph.NHNH^.HCl on 2'-hydroxychalcones and llavanones in pyridine me-

dium.

69

HX

OH

C-CH=CH

O ^ @ ) - R

Ph.NH.NH,.HCl

Pyridine

,()H

^ - ^ < O V K Ph

Jamode -'̂ reported the formation of 2'-hydroxychalcone phenylhydra/.one by tlic ac-

tion of hydrazine hydrochloride on llavanones and its conversion into 3,5-diaryl-l-

phenylpyrazolines.

.OH Ph.NH.NR.HCl

NH,(CH3),NH,

HtOH

-> -9,-CH=CH/O) N ^—

NH-Ph

DH

%'̂ Ph

70

Wadodkar^" furlher reported the synthesis ol" 3,5-diaryl-l-phenylpyra/.olines from

flavanones and phenylhydrazinehydrochoride in DM!-.

[Ol •°V-KQ) II

y - N f 1 > f U k M U M U VX{^\ J.I ir

PhNHNH,HCl -$>

O DM I-%'^

Ph

Gamil Aziz et aP' have reported the formation of A--pyrazolines and their correspond-

ing isomers by the action of hydrazine hydrate on furochalcones in acetic acid and ethanol

respectively. A--pyrazoline derivative have also been prepared by the action of

phenylhydrazine on furochalcone.

R

' S j / * - (;;-CH=CH-^o)> OCHP

Ph.NH.NH, EtOH/AcOH

R

Qoj. OH CiL

HXO I

NH.NH,

ACOH V%> H

R

71

Cyclocondensation of RCCl=N.NH.Ph lo irisubsliliiled alkene R'CH=C'HS( )J'h gave

pyrazolines^^

R'-CH=CHSO,Ph+RCCl=NNH.Ph- -» N

R

I

^ N-R'

SO.I'h

Chincholkar and Jamode (1979)" have reporied the synthesis of some new 4-

aroylsubstituted pyrazolines by the condensation of hydrazinehydrate and phenylhydrazine

with 3-aroylflavanones in pyridine.

R ,OH

(): .-^oX^ NH,NH,H,0

Pyridine -> N.'̂ R-

Ph

The synthesis of l-phenyl-3-aryl-4-aroyl-5-(2-hydroxyaryl)-pyra/.oline by the con-

densation of 3-aroyUlavanones with Ph.NH.NH, in methanol was also reporied by

Chincholkar and Jamode '̂*.

Ri

R' ^-^CH X

X o 6

- ^ ' ' ^ < ^ ' '

Joshi and Wadodkar (1982)'''̂ reported the fomiation of 4-bromo-3- (2'-hydroxyphenyI)-

72

1,5-diphenyl-pyrazolines from 3-(2'-hydroxyphenyl)-1.5-diphenylpyrazolincs and NliS in

ccr. 4

KLy\P^ Ri - '̂ ^"

R=' ̂ -^^c , NBS R' ^^ C < > II

h I ' l l •

Kale et al '̂'{1984) has synthesised 3,5-diphenyl-l-(3,5-dichloro) salicyloyl pyra/olines

from 5.2-R(OH) qH,COCH;CHC,H,R,Rj with 3,5,2-Cl,(OH)C;_HX()NH.NH, in DMF .

II

I Reddy et a l" synthesised 3-arylsull'onyl-2-pyra/.olines by cycloaddilion ol

diazomethane to arylvinylsulphones in the presence of triethylamine at ()"C.

EtN

ArSO,CH=CH, + CH,N, Ar(),S-C

()"C;48 hrs.

1 H

73

Ozawa el aP** reported the synthesis ofpyrazoline which was found lo he very elTec-

live in killing housellies an contact.

CXNR.R,

Van Hes el aP^ synthesised pyrazoline which was Ibund to have insecticidal proper-

lies.

R> o

%

C-NH-

ricidal, pharmaceutical and fungicidal agent.

R,

H,N-C-

%

-R,

/

R

Copp et al"*- reported the synthesis of substituted aminopyra/.olines with

cycloenaseinhibiting activity.

R ' -C r—R'

R - % ^ NRiR-̂

The synthesis of pyrazoline from chalcone and NH^-NH^. I'hNHNH, and

Ph.NHCONH, through epoxyketones was reported by lU-Hashash et a!"'.

Me.HC

C r

N NH

. ^ / ' ^ • ' N

Solvent (dry ether)

,/N(),

Hammounda, H.A. and Hussain S.M/"' reported the synthesis of new heterocyclic

compounds bearing a pyrazole moiety on isoxazoline and pyra/.oline ring from 4-cinnamoyl-

1,5-diphenyl-3-methylpyrazole.

Ph r

Ar

H-

H,COC J L CH

Ph Ph. A

" = Hrof̂ J IL c ArHC = HCOC RNH.NH NH.OH.HCl

Ph Ph ̂ /^k

I

OH/EtOH

Ar

Ph

CH, jjt ai.„.

H

76

Sachchar, S.P. and Singh A.K/" synlhesised some new lluorinated

heleroarylpyrazolines from chalcone derivatives and found lo posses bactericidal and fungi-

cidal activity.

R' C

II (R=2-furyl. 2-lhienyl. 2-pyridy

& R'=H.Me,CK-()H)

Ph

Nair*^ reported the synthesis of 3-(2"-hydroxyphenyl)-5-(2'-furyl)-pyra/.olines and 3-

(2'-hydroxyphenyl)-5-(2'-furyl)-N-acetylpyrazoIines from P-(2"-l"uryl)acrylphenones and

hydrazinehydrate in ethanol and acetic acid respectively.

Fahmy et aF** have synthesised a scries of substituted pyrazolines by the action of

hydrazine on N-arylidine-4'-amino chalcones. The antibacterial and fungicidal activity of

pyrazolines synthesised have also been reported.

Suratkumar and Rastogi"'-* reported the anti-implantation activity of 4._S-irans/cis-l-

acetyl-3,5-diaryl-4-phenylpyrazolines.

K ^ / V I

°'-\ O] lO^

•R

SaraP (1988) synthesised some new 5-phenyl-3-(2-hydroxy-4-oxo-4-H-1 -ben/.opyran-

3-yl)-A--pyrazoline-l-carboxamides from 3-cinnamoyl-2-methylchr()mones and

'H

semicarbazide hydrochloride in ethanol containing a liltle acetic acid.

NH,NHCoNH,

t

Ankhiwala. M.D. and Naik, H.B.^' haN'c prepared pyrazolines by cyclocondensaiion

of 2.4-OH(BuO)CgH^COCH:CH-R with phenylhydrazine in acetic acid or hydroxylaniine

in ethanol. The compounds were screened for bacterial activity.

BuO o

6 -CH=CH-R

Ph.NH.NH,

AcOH

BuO^^'X/OH

H AR \ I

Ismail et al" have synthesised the substituted pyrazolines by the reaction of 4-

RC,H,COCH:CHC,H^R, with R.NH.NH,.

N R'

(R=MeO, Cl;R'=3,4-()CH,{).4-Me();R,=H.Ph.Br,,S()J'h etc.

78

Noll Bernd et al'*"' reported the synthesis of trimethyl ammonioethoxy ethyl

sulphonylphenyl-4-chlorophenylpyrazoline salts which was found to be very elTective her-

bicide.

C,H,SO,CH,-R

Ankhiwala, M.D. and Naik, H.B.''^ prepared substituted pyra/oline by

cyclocondensation of Ph.NH.NH, with the corresponding

RqH^CH:CHCOC,H2(NO,)(OBu)-OH-5.4,2. which were found to be effective herbicides.

(R=H.2-B,,4Me3N)

Holla, B. Shivarema''̂ have reported the synthesisof chlorosubstituted pyia/.oles and

pyrazolines by cyclization of p-chloro C,H^CH(Br)-C(0)R with R'C(0)NH.NH,.

Ayoub, Mikdodt""̂ reported the synthesis of some substituted 3-aryl-5-meihy!-(or 4,5-

dimethyl)-2-pyrazoline from chromones with hydrazine.

79

Section B

i) Synthesis of3-(2-hydroxyphenyl)-4-aroyl-5'aryl-A^-pyrazolines (5a-I) :

a, 3 - Unsaturated carbonyl compounds like chalconcs or llavanones reacts with

hydrazine or phenylhydrazine to yield hydrazones which cyclises to corresponding A--

pyrazolines'''^^-^ Flavanone hydrazones have not been reported bul llavanone

phenylhydrazones^'''^^'"^ have been reported in literature. 4-aroyl-3,,'S-diaryi-l-

phenylpyrazolines have been synthesised from 3-aroyinavanones in pyridine" and their

iosmeric pyrazolines in methanoP". Chincholkar*''' also reported the formation of 3-(2-

hydroxyphenyl)-4-aroyl-5-aryl-A^-pyrazolines from 3-aroyltlavanones and hydrazine

hydratein pyridine. Thakare" reported the use of methanol to synthesize same 3-{2-

hydroxyphenyl)-4-aroyl-5-aryl-A2-pyrazoIines from 3-aroyinavanohes and hydrazine hy-

' drate. Recently Ramekar̂ ** has used Dioxane containing piperidine as a solvent for the prepa-

ration of 3,5-diaryl-4-aroylpyrazoline from 3-aroylflavanones and hydrazine hydrate.

The work presented here deals with the synthesis of six new 3-(2-hydroxyphenyl)-4-

aroyl-5-aryl-A^-pyrazolines (5a-f) from 3-aroylflavanones (4a-f) and hydrazine hydrate in

DMSO containing little piperidine.

Experiment No. 13

Action of hydrazine hydrochloride on 3-benzoyl-6-methylflavanone (4a) :

Synthesis of3-(2-hydroxy-5'methylphenyl)-4-benzoyl-5'phenyl-A^-pyrazolines (5a) :

Mixture of 3-benzoyl-6-methylflavanone (4a) (0.01 mol, 3.42 g.) and hydrazine hy-

drochloride (0.02 mol, 1.37 g.) was refluxed in DMSO (15 ml) containing piperidine (0.5

ml) for 4-5 hr. The cooled reaction mixture was diluted with water and acidified by 1:1 HCI

99

(15 ml) when a semisolid was isolated. The product was triturated with and crystallised

from ethanol to get compound (5a), m.p. 145-146°C yield 70%.

Reaction :

OH

Y\0/ NH.NH^H.O HX'^S^C /o)

CO * " > " ' T

DMSO/Piperidine ^ ^ N - ^ O , H

(4a) (5a)

Properties and constitution of the compound (Sa) :

1) The compound melted at 145-146»C.

2) The compound (5a) gave dark green colouration with ethanolic 1-eCI, solution.

3) The compound was soluble in dilute NaOH, indicating the presence of phenolic

-OH group.

4) The paper soaked in the solution of the compound (5a) in benzene turned bluish green

. when exposed to bromine vapour (Knorr's test for pyrazolines).

5) The compound (5a) gave deep blue colouration with cone. H ŜO .̂

6) The analytical data confirmed the molecular formula of the compound (5a) to

be qjH^oN^O,

7) Elemental analysis of the compound (5a):

100

Analysis %C %H %N

Found 77.15 5.32 7.72

Calculated 77.52 5.60 7.87

From the properties and analytical results, the compound (5a) was assigned the struc-

ture as 3-(2-hydroxy-5-methylphenyl)-4-benzoyl-5-phenyl-A--pyrazoline.

OH / O r -C=0

H NMO)

Mechanism of the reaction :

The mechanism of the reaction involves the nucleophilic attack of the basic nitrogen

on the carbonyl groups. The protonation of the carbonyl oxygen makes the carbonyl carbon

more susceptible to necleophilic attack. Thus where the carbonyl group is concerned, high

acidity is favoured, but at such pH, hydrazine also undergoes protonation forming NH .̂NH,

which is no longer a nucleophile. Thus for the necleophile low acidity is preferred therefore

the pH of the reaction must be adjusted in most cases. The reaction medium must be just so

acidic as to allow for the protonation of an appreciable fraction of the carbonyl compound

and not so acidic as to cause a low concentration of the free nitrogen compound. The exact

conditions depend upon the basicity of the reagent and the reactivity ol" the carbonyl com-

pound.

The reaction probably proceeds via an intermediate hydrazone which cyclises to form

101

the pyrazoline. Thus the reaction may be shown as the nucleophilic attack of NH,.NH, on

the carbonyl group of the flavanone, followed by the formation of the hydra/.onc (noi iso-

lated) which under experimental conditions cyclises to form the 3-(2-hydroxy-5-

methylphenyl)-4-benzoyl-5-phenyl-A^-pyrazoline(5a).

NH.NRKO -^

DMSO/Fiperidine .OH

OH O

NH,NH'

r -̂

@0H t

NH,

Mixture of 3-benzoyl-4-methoxy-6-methyl-navanone (4b) (0.01 mol, 3.72 g) and

hydrazine hydrochloride (0.02 mol, 1.37 g) was retluxed in DMSO (15 ml) conianing

piperidine (0.5 ml) for 4-5 hr and processed as in Expt. No. 13 The product thus obtained

was crystallised from ethanol to get crystals of compound (5b) , m.p. I7()-l7i"C, yield

85%.

" 3 ^ ^ ^ ^ ; ^ \ 0 / DMSO/Piperidine ' ^ V i < 0 ) > O C H ,

(4b) (5b)

Properties and constitution of the compound (5b) :

The compound (5b) melted at 170-171"C.

The compound (5b) showed properties similar to those given in Hxpt. No. 13.

Analytical results of the compound (5b) agreed with the moleculai' fomiula C^H^N^O,.

Elemental analysis of the compound (5b):

Analysis %C %H %N

Found 74.41 5.37 7.01

Calculated 74.61 5.60 7.25

The spectral data of the compound (5b) is as follows :

a) The frequencies observed in IR spectra of compound (5b) (vSpeclrum No. 10) arc

located as follows:

03

I ' .

o ' o ^ •

o : o

35" o

I I

X o

^

o

E

l-< 4-1 O a a en

TOT 1 NH.NH,

R̂ O

Sangwan et al" reported synthesis and biological properties ol" 2-pyra/olines by

cytiization of hydroxymethoxychalcones. R C ; H ^ C ( X ^ H : C H C ; H / ) M C - 4 (I;R=2-( )H. I -OH)

with hydrazine hydrate in formic in acetic acid.

COR'

/ V N — N

MuUer el aP" prepared 4-aminoethyl-2,5-diphenyl-2,4-dihydro-3-H-pyrazt)line-3-one

as herbicides.

^ CHR'R^

R̂ O

Comp : R,=H, alkyl,R,=H,0H,NH3, haloalkyi, haloalcoxy etc.

R3=(F,HC0)qH^, (F,HCS)qH^

R^=(Substituted Ph)

T. Subai, Shiniche et al'''̂ reported the preparation of (phcnylaminocai'bonyl)-pyrazoline

which was found to be effective insecticide. It's insect mortality in 7 days of 3-insiar larvae.

80

Spodoptera-litera when applied to the leaves of sweet potato plants at 40 ppni cone.

ioNH -/oV"^

(R'=R2=x=H.Y=C,3())

T. Subai, Schinichi el aP reported the synthesis of (Phenyl carbamoyl) pyra/.t)line

insecticide.

ioNH - < p ) - Y H

A=(un)substituted Ph, halogen substituled,3-pyridyl;

B-=(un) substituted Ph, halogen substituted, 3-pyridyl;

Xand Y=H, halogen (halogen substituted) C, _, alkyl, such that X=Y>or A & B is halogen

substituted C, _, alkyl produced 100% mortality of Spodoptera-litera larve alter 7 days.

Gallen Kamp, Bornd et al̂ ' reported the synthesis of substituted pyrazolines.

:i

H I R̂

(a) (b)

R,,R3=(un) substituted,aryl,heteroaryl; R,=H; alkyl, cycloaikyi aryl)

(a) are intermediates for insecticides (b) is an iniermediale lor R^=(C{)NHC^H_,()CH1\ _,)

Subbanwad, G.R. and Vibhule, Y.B.". reported the synthesis of some new pyra/olines

and N-phenylpyrazoIines. The compounds were tested lor antibacterial and aniilungal ac-

tivities.

I

R--

R'

Trivedi, RB. et a F synthesised pyrazolines derivatives of phenothia/.ine. a/.etidiryl,

aminoacelyl derivative, arylmalonamylhydra/.ido derivative and diaryl pyra/olinylacetyl de-

rivatives which were tested for antimicrobial activity. Compounds exhibit moderate to good

antibacterial and tuberculostatic activity.

R'NHN ^ R R'NHN

o 0'

R

CI

R'-N N̂

Orlov, V.D. Getmanskii, N.V. et al̂ "* reported pyrazoline derivatives of 2-nitrochalcone

by its condensation with N,H^ in MeOH. EtOH or Me,CH()H

NO,

H,NN

(R=H,Ac. Br„ OMe)

82

Van Almsick Andreas et aK'"" synihesised pyra/.olincs and were used as (X'siicides

R^=R^=Ph, substituted Fh.R^=l'h, cyclohexane.

R^=H,alkyl.

R R-

' N •N' N> ̂ N'

O NR^P^ H

Ogawa Nuryoshi Takada, Knayama Soloshi"' prepai'ed pyra/.oline coniainini! liisphenol

derivatives as intermediates for polymers.

R' R' K'

C ^

R''

HO I \ 4 I R' I OH

EtN

Koy NEt.

(R|-R^=H,halo, etc, one of the R„ and Rjn is a pyra/.oline containing

moiety the other is H. alkyl etc. )

Rao el al*' prepared pyra/.oline enamines iVom 3-acetyl-4-aryl-2-pyra/oiines a series

of acyclic and cyclic pyrazoline enamines were obatined from benzalaceiones through the

corresponding 2-pyrazolines.

83

(R=H.Me,OMe).

Rao et a P reported the synthesis and chai"acterization of some 3,4-diaroyl-2-pyrazolines

by cycloaddition of diazomethane to 1,4-diaryl-2-butene-1,4-diones.

Romich, F.A., Hussein M.M. et al̂ ^ reported synthesis and biological activities of

certain N-substituted-3-iTiethylpyra/.olines -5-one. The pharmacological study of these com-

pounds showed significant analgesic and antiinflammatory activity.

Modi et al™ synthesised l-phenyl-3-(2"-hydroxy-4"-methoxy-5"-nitrophenyl)-5-sub-

stituted phenyl 2-pyrazolines from the coresponding chalcone derivatives and

phenylhydrazine.

MeO^

(lunaydin et aF' synthesised 3-(3,5-dimethyl-2-furoyl)-4-aryl-5-carbathoxy-A--

pyrazoline by the dipolar cycloaddition of 3,5-dimethyl-2-furoyl-p-substituted siyiylketones

and cthyldizoacelate.

Bologa, Ursulal, Musat. Cornea; et aP- reported synthesis and NMR spectra of 3-(3.5-

84

dimethyl-2-furanyl)-l,5-diaryl-A--pyrazolines from cycloaddiiion of 3,5-dimeihyl-l,2-

aceiylfuran with aromatic aldehydes affords chalconc analogs followed by condensaiion

with PhNHNH,.

Thakare" reported the synthesis of 5-aryl-3-(2-hydroxyphenyl)-A--pyra/olinc.s from

2'-hydroxychalcones and hydrazine hydrate in ethanol and isomeric -3-aryl-5-(2-

hydroxyphenyl)-A--pyrazolines in DMF.

' O

NH,NH.H,0

EtOH

NHNH,2HC1

DMF

0>R

H- - N ' ^ X O / ^

Gudadhe^^ has reported the synthesis of 3-(2-hydroxy-3-iodo-5-methylphenyl)-5-aryl-

A^-pyrazolines from chalcones and flavanones on treatment with hydrazine hydrochlorides

in elhanol containing little piperidine.

< 0 > C - C H = C H ^ " 3 ^ O NH.NH^HCl

85

Modi and Naik '̂' have synthesised some new l-H-3-(2'-hydroxy-4'-mcihoxy-5'-

bromophene-l'-yl)-5-Subsliluled phenyl-2-pyrazolinesand iheir acetyl and benzoyl denva-

lives.

Bilgin el aF*" have reported synthesis and antidepressant activity of some I-

thiocarbamoyl-3,5-diphenyl-2-pyrazolines.

Rajput" has prepared -5-ai7l-3-(2-hydroxy-3-chlorophenyl)-1 -phenyl-A^-pyrazolines

from 2'-hydroxy-3'-chlorochalcones and phenylhydrazine hydrochloride in elhanol containm^

'little piperidine. The same pyrazolines were also obtained from I'lavanones and

phenylhydrazine hydrochloride in ethanol containing little piperidine.

.OH CI

Ph NHNH HCl • ^ H,C

OH

EtOH/ piperidine

N N I Ph

o

Ramekar'*' has synthesised 3,5-diaryl-4-aroyl-A'-pyrazolines by the action ol V

aroylOavanones with hydrazine hydrate in dioxane in presence of little piperidine.

OVOCH3 + NRNH H,()

Dioxane Piperidine H,C ii

/OH XQ)

N N I Ph

0>-OCH

86

Sonare and Doshi™ ha.s reported the synthesis of 1 H-3-(2'-hydn)xy-4'-melh()xyphenyl)-

5-subsliluled phenyl-2-pyra/.olines from 2'-hydr()xy-4'-melhc)xychalf()nes. Iliorc ci aP' have

synthesised pyrazolines from the chalcones ol' I,4-dihydro-2,6-dimelhyI-4-{SubsiiiLiied

phenyl)-3,5-diacetylpyridine and tested them tor their antimicrobial .activity. I'alil*" has re-

.poried the synthesis of chlorosubstituted 3,5-diaryl-4-aroyl-l-phenylpyra/.olines from 3-

aroyl-chlorosubstituted flavanones and phenylhydra/.ine hydrochloride in DMl- solvent con-

taining few drops of piperidine.

Deshmukh, M-S.**- has reported the synthesis of 5-aryl-3-(2-hydroxy-3.5-

dichlorophenyl)-!-Phenyl-A^-pyrazolines from 2'-hydroxy-3',5'-chlorochalcones and phe-

nyl hydrazine hydrochloride in DMSO containing a little piperidine.

Recently Kedar**̂ has reported the formation of 3.5-diaryl-A--pyrazolines and 3..S-

diai'yl-4-aroyl-A--pyrazolines from 2'-hydroxyclialc()nes and 3-aroyinavan()nes respectively

by the reaction with hydrazine hydrate in ethanol containing little piperidine. He also re-

ported the synthesis of l-carboxamido-3,5-diaryl-A--pyrazolines and l-carboxamido-3,5-

diaryl-4-aroyl-A--pyrazolines from chalcones and flavanones by the reaction with

semicarbazide hydrochloride in ethanol.

87

Origin of Problem

The literature reveals the importance ol" pyra/.olines as bleachiny aiienis and

Juminescents apart from their use as drugs. The most convinient method of synthesis of

pyrazolines involved the action of hydrazine or phenylhydrazine on a,P-unsaiuiated caibonyi

compounds. The reaction leads through the intermediate phenylhydra/.one which can sub-

sequently cyclise to pyrazolines'' with suitable cyclising agent. The most convinient reagent

for cyclization of hydrazone is acetic acid\ It has been reported that pyridine when used,

does not retard the conversion of syn-form of phenylhydra/.one to pyra/.olines. Kalley el al"

reported that the tlavanonehydrazone is not an intermediate of pyra/.oline formation in the

reaction of tlavanone & hydrazine.

Borkhade and Marathe-^ have used pyridine as a medium in the formation ol 3.5-

diarylphenylpyrazoline from 2'-hydroxychalcones and flavanones on treaimeni with

phenylhydrazine, without isolating the intermediate. Jamode"'̂ reported the fiHiiiaiion ot 2'-

hydroxychalcone phenylhydrazone intermediate by the action of phenylhydra/me hydro-

chloride on 2'-hydroxychalcones and tlavanones in ethanol solvent in presence ol

ethylenediamine (50%).

Chincholkar and Jamode'^ reported the formation of 4-aroylsubstituted pyrazolines

by using pyridine as a medium Kakade and Jamode'*'' reported synthesis of pyrazolines by

using DMSO as a solvent. Rajput" reported the formation of 3,5-diaryl-A--pyrazolines m

ethanol containing little piperidine. Patil*" prepared 4-aroylchlorosubstituted pyrazolines

from 3-aroylflavanones with NH^.NH^.HCI in dioxane piperidine mixture 3.5-

diarylpyrazolines"- were also prepai'ed from 2'-hydroxy-3.5-dichlorochalcones usmg I )MS()

containing piperidine as a solvent. Ramekar'** has synihe.si.sed 4-aroyl-suhsiiiuied pyrazolines

88

by condensing 3-aroylflavanones with NHj.NH^.HCl in dioxane contaning liiilc pipcridine

as the solvent.

Similarly there are very few references of the reactions of semicai'ha/.ides with caibonyl

compounds. El. Hashash et a P reported the formation of l-carhoxamidopyra/olines from

epoxyketones and semicarbazides. Thakare'' reported synthesis of l-carhoxainido-3.5-

diarylpyrazolines from 2-hydroxychalcones and semicarba/.ide in ethanoL However, the

same reaction in DMF yielded 3-ai7l-5-(2-hydroxyphenyl)-A--pyra/.olines. Reccnily Kcdar**'

reported the synthesis of l-carboxamido-3,5-diaryl-A^pyrazolines & i-carboxaniido-3.5-

diaryl-4-aroyl-A--pyrazoIines from chalcones and llavanoncs respectively by reaction with

semicarbazide hydrochloride in ethanol.

From the foregoing account, it was thought interesting to synihesi/.e the 4-

aroylsubstituled pyrazolines from 3-aroyinavanones and hydrazine hydroch)ride in DMSO

containing little pipcridine and also to study the reactions of 3-aroyIflavanones with

semicarbazide hydrochloride in ethanolic KOH to synthesis l-carboxamido-3-(2-

hydroxyphenyl)-4-aroyl-5-aryl-A--pyrazolines.

Problem

The present work deals with the synthesis of 3-aroyinavanones and their interaction

with hydrazine hydrochloride in DMSO containing pipcridine to get 3-(2-hydroxyphenyl)-

4-ai"oyl-5-aryl-A--pyrazolines.

This part also reports the study of the reactions of semicabazide hydrochloride with 3-

aroylfiavanones in ethanolic KOH. Thus relluxing of 3-aroyl-flavanones with ,seniicarba/.idc

hydrochloride in ethanolic KOH afforded l-carboxamido-3-(2-hydroxyphenyl)-4-aroyi-5-

aryl-A--pyrazolines.

89

Summary of the work

2-Hydroxyacetophenone: (1)

2-hydroxy-5-nielhyl-acetophenone (la) and 2-hydr()xyaceU)phcm)nc (lb) were ob-

tained respectively from p-cresylacelale and phenylacelale by I'lies IVIigialii)n.

2-Aroyloxyacetophenone: (2)

2-Benzoyloxy-5-methylacetophenone (2a) and 2-benzoyloxyaceiophenone (2b) were

obatined by benzoylation of respective acetophenones using benzoic acid and POCl, m

pyridine medium.

l-(2-Hydroxy-5-methyl-phenyl)-3-aryl-l,3-propanedione (3) :

l-(2-hydroxy-5-methylphenyl)-3-phenyl-l,3-propanedione (3a), m.p.yO'C. and l-(2-

hydroxyphenyl)-3-phenyl-l,3-propanedionc, m.p. 125"C. were prepared by Baker-

Venktaraman Trasformation of corresponding 2-aroyIoxyacelaphenones. The siruciurc ol

(3a) was confirmed on the basis of IR, U V and PMR spectra and discussed in pari-1. cChapicr-

II of the thesis.

3-Aroylflavanone(4) :

3-Aroylflavanones (4a-f) were prepared from l-(2-hydroxy-5-methyIphcnyl)-3-phe-

nyl-13-propanedione (3a) and l-(2-hydroxyphenyl)-3-phenyl-l,3-propanedionc (3b) by

interaction with appropriate aromatic aldehyde in ethanol containing few drops of piperidine.

The structure of 3-benzoyl-6-methylflavanone (4a) was comfirmed on the basis of IR. UV

and PMR spectra and discussed in the part - 1 , chapter II of the thesis. The compounds (4a-

f) thus prepared are tabulated in Table I. I

4-Aroylpyrazoline: (5) :

3-Aroylflavanone (4a-f) on treatment v/ith NH,NHC()NH, in eihanolic KOH gave I-

90

carboxamido-3-(2-hydroxyphenyl)-4-aroyl-5-arylpyra/,olincs (6a-l). The slriicuiie ol U

.carboxamido-3-(2-hydroxy-5-methylphenyl)-4-benzoyl-5-phenylpyra/oline (6a) was con-

firmed on the basis of IR, UV and PMR spectra and discussed in section B in chapter 11 of

part II of the thesis. The compounds (6a-0 thus prepared are tabulated in 1.3.

Table 1.1

3-Aroylflavanones

Comp.No. Expt. No. 3-Aroylflavanones m.p. "C

3-B^n/s)yl-6-methyinavanone 14X

3-Benzoyl-4'-methoxy-6-methyinavan()ne 15S

3-Benzoyl-2-(2'-furyl)-6-methylchromanone 125

3-Benzoyinavanone 153

• 3-Benzoyl-4'-methoxynavanone 122

3-Benzoyl-2-(2'-furyl)chromanone 144

4a

4b

4c

4d

4e

4f

7

8

9

10

11

12

Table 1.2

4-Aroylpyrazoline (5)

Comp No. Expt. No. 4-Aroylpyrazoline ni.p. "C.

5a 13 3-(2-Hydroxy-5-melhylphenyl)-4-ben/.oyl-5 145-146

-phenyl-A^-pyrozolinc

5b 14 3-(2-Hydroxy-5-melhylphenyl)-4-bcn/.oyl-5 170-171

-(4'-melh()xyphenyl)-A-pyra/.()linc

5c 15 3-(2-Hydroxy-5-niclhylphcnyI)-4-ben/.oyl-5 160

-(2'-furyl)A--pyra/oline

5d 16 3-(2-Hydroxyphenyl)-4-benzoyl-5 15!

-phenyl-A--pyrazoline

5e 17 3-(2-Hydroxyphenyl)-4-ben/,oyl-5 I3K

-(4-methoxyphenyl)A--pyrazoline

5f 18 3-(2-Hydroxyphenyl)-4-benzoyl-5 160

-(2'-furyl)-A--pyrazoline

92

Table 1.3

l-Carboxamido-3,5-aryl-4-aroyIpyrazollne

Comp.No. Expt. No. l-Carboxamido-3,5,diaryl-4-aroylpyrazoIine m.p. "C.

6a 19 . l-Carboxamido-3-(2-hydroxy-5-methylphenyl) 171

-4-benzoyl-5-phenylpyi"azoline

6b 20 l-Carboxamido-3-(2-hydroxy-5-melhylphenyl) 163

-4-benzoyl-5-(4'melhoxyphenyl)pyrazoline

6c 21 l-Carboxamido-3-(2-hydroxy-5-methylphenyl) 150

-4-benzoyl-5-(2'-furyl) pyrazoline

6d 22 l-Carboxamido-3-(2-hydroxyphenyl) 150

-4-benzoyl-5-phenylpyiazolinc

6e 23 l-Cai-boxamido-3-(2-hydroxyphcnyl) 142

-4-benzoyl-5-{4'-methoxyphenyl) pyrazoline

6f 24 l-Carboxamido-3-(2-hydroxyphenyl) 151-152

-4-benzoyl-5-(2'-l'uryl)pyrazoline.

93

Paff II

CHAPTER -II

Contents Page No

Discussion of the Results and Experimental 94

References 127

Chapter II

Experimental and Discussion of the Results

Review of the literature shows that the formation ol' pyra/oline I'rom chalcones and

flavanones takes place in basic medium. The most convenient method lor ilie synthesis ol

pyrazolines involves the interaction of hydrazine or phenylhydra/.ine and a,(3-unsatinaled

carbonyl compounds. Borkhade and Marathe-** used pyridine as basic medium ni ihe forma-

tion of 3,5-diaryl-l-phenyipyrazolines by the action of phenyihydrazine hydrochloride on

2'-hydroxychalcones and flavanones. The treatment of phenyihydrazine with

benzalacetophenone in acetic acid gives 3,5-diaryl-l-phenylpyra/.oline\ But in case ol

hydrazine the side products like azines and hydrazones are formed**". Sammour et aF' re-

ported the formation of 3-ai7l-1,5-diphenylpyrazolines from chalcones and phcnylhydra/ine.

DMF^° and ethylenediamine-'^ have been used as a basic medium in the synthesis of

pyrazolines from flavanones , chalcones and phenyihydrazine hydrochloride. Kakade and

Jamode*** reported the use of dimethyl sulphoxide (DMSO) solvent in the synthesis of 3.5-

diaryl- 1-phenylpyrazolines. Thakare" reported the synthesis of 5-aiyl-3-(2-hydroxyphenyl)-

A--pyrazolines from 2'-hydroxychalcones and hydrazine hydrate in elhanol and isomeric 3-

aryl-5-(2-hydroxyphenyl)A--pyrazolines in DMF. Chincholkar and Jamode'* have synthe-

sised some new 4-aroylsubstituted pyrazolines by the condensation of hydrazinehydrate

and phenyihydrazine with 3-aroylilavanones in pyridine medium and isomeric pyrazolines

in methanol. From the literature it has been observed that, piperidine as a basic medium has

not so far been used in the synthesis of 3,5-diaryl-A--pyrazolines from 2'-hydroxychalcones

and flavanones using phenyihydrazine hydrochloride or hydrazine hydrate or hydrazine

hydrochloride.

94

The mechanism of the formation ol" pyra/oline suggests that it necessarily proceeds

through the formation of an intermediate hydrazone or phenylhydra/.one. This inierniediaie

on subsequent cyclization yields the corresponding pyra/oline. It is often necessary to ad-

just pH of the reaction medium. The addition of hydrazine or substituted hydrazine to caibonyl

group involves the nucleophilic attack by the basic nitrogen on carbonyl carbon. I'roionalion

of a carbonyl oxygen makes carbonyl carbon more susceptible to a nucleophilic attack. In

carbonyl compounds the addition will be favoured by high acidity, liut the hydrazine or

phenyl hydrazine can also undergo protonation to form the ion NH^NH,* or I'h.NH.NH,

which lacks unshared electrons and is no longer a nucleophile. Thus, so far as nitrogen

compound is concerned the addition is favoured by low acidity. The conditions under which

addition proceeds most favourably are the result of compromise, the solution must be acidic

enough for an appreciable fraction of the carbonyl compound to be protonaled. but not so

acidic that the concentration of free nitrogen compound is too low. The exact condition used

depends upon the basicity of the reagent, and upon reactivity of the carbonyl compound.

: C = 0 ^ ^ ^ C - O H "?^"^ ' > ^C-OH > >C=N-( i + H2.O

I H

H^N-G ;; ^ Hj-N^-G

Free base Salt not

nucleophile nucleophile

where G=NH,, Ph.NH, OH, CI.

Piperidine (Kb = 2xl()-^) has the usual basicity of a secondary amine. Like pyridine

95

(Kb=2.3 X 10'^), it is often used as a basic catalyst in reactions like Knoevenagel reaction,

Michael addition etc. Piperidine appears to satisfy the necessary conditions required for

nucleophilic addition. One may imagine that it makes carbonyl carbon more susceptible U)

a nucleophilic attack. It must be enhancing the nucleophilicily of hydrazine hydrate or

hydrazine hydrochloride favouring the nucleophilic attack on partially positively charged

carbonyl carbon. It was thought interesting therefore, to make use of piperidine in the syn-

thesis of A" pyrazolines from 3-aroyinavanones.

This part of the thesis deals with the .synthesis of 3-aroylflavanones. The various meth-

ods used in the synthesis of llavanones have already been discussed in Section A of i'ART-

I of this thesis. In particular 3-aroyinavanones can be conveniently synlhesised from l-(2-

hydroxyphenyl)-3-aryl-l,3-propanediones by condensing them with aldehydes in ethanol

in the presence of piperidine**''.

These 3-aroylflavanones were reacted with hydrazine hydrochloride in DMSO con-

taining little piperidine to get 3-(2-hydroxyphenyl)-4-aroyl-5-aryl-A^-pyra/.olines.

This chapter also includes the synthesis of l-carboxamido-3-(2-hydroxyphenyl)-4-

aroyl-5-aryl-A--pyrazolines from 3-aroyinavanones and semicarbazide hydrochloride in

ethanolic KOH.

The compounds have been characterised on the basis of chemical properties, elemen-

tal and spectral analyses. The.melting points were recorded on 'Tempo' melting point appa-

ratus and are uncorrected. The carbon and hydrogen analysis was carried out on 'Carlo lirba

1106' analyser. The nitrogen estimation was done on Xoleman N analyser-29'. The infrared

spectra were recorded in 'Ferkin-Elmer 202' spectrophotometer in KBr pellets. The ultra-

violet-visible spectra were recorded in chloroform on 'Ferkin-lilmer 202' specii-ophotomeler.

96

The proton magnetic resonance spectra were recorded on Terkin -lilmer R-^2' using TMS

as reference in CDCl̂ . The elemental and spectral analyses were carried out at RSIC. IIT,

Bombay. The chemicals used were of laboratory reagent grade and purity ol compounds

synthesised were tested by thin layer chromatography on microscopic slides with silica gel-

G layers of 0.3 mm thickness.

97

Section A

Preparation of Starting Materials

The preparation of starting material involves the following steps :

i) The preparation of 2-hydroxyacetophenones (la and lb).

ii) The preparation of 2-benzoloxyacetophenones (2a and 2b) from

2-hydroxyacetophenones (1 a and 1 b).

iii) The preparation of l-(2-hydroxyphenyl)-3-phenyl-l,3-pn)panediones

(3a'and 3b) from 2-benzoyloxyacetophenones.

iv) The preparation of 3-benzoyinavanones (4a to f) from I-

(2-hydroxyphenyl)-3-phenyl-1,3-propanediones.

The detailed procedure and the connected account for the preparation of above com-

pounds is given in Section A of Chapter II in Part - i of this thesis under \i\p[. No. I lo 12

98

x-z

£

c

J L _l U J L.

imii i iui: » ^O ^

1

. i

1

• "

1 1 1 1 p 01

* * i 1 1 t

i * y

\ \

.

t i ff

•K i *

•u u OJ a

CO

Region(Cm')

3700-3000

3000-2800

1790-1600

1600-1450

Frequency

3500

3020-2900

1650-1630

1585

Intensity

(w.b)

(w,b)

(w)

is)

Correlation

0-H slielching

N-H stretching

C=0 stretching

of COFh group

C=N stretching

ofpyra/.oline

b) The UV-VIS spectrum of the compound (5b) (Spectrum No. 11) recorded in CHC'l, showed

max at 270 and 375 nm which indicates carbonyl function.

c) The PMR spectrum of the compound (5b) (spectrum No. 12) recorded in CDC'I, gave

following important chemical shifts.""̂ "'̂ "

Chemical Shift

in 5

2.34

3.75

5.1

5.9

6.8

6.98

7.26-7.8

Nature of

peak

(s)

(s)

(d)

(d)

(d)

(d)

(m)

No. of Type of

protons protons

3H

3H

IH

IH

IH

IH

lOH _

Ar-CH,

Ar-OCH,

^ B f

H^

Ar-H

. On the basis of properties, elemental analysis and spectral results, compound (5b)

was assigned the structure as 3-(2-hydroxy-5-methylphenyl)-4-ben/oyl-5-(4-

methoxyphenyl)pyrazoline.

104

/§) I

c=o ko> OCH,

(5b)

It has been observed that the electron donating group such as -OCH, at 4'-po,siii()n of

the side phenyl ring in flavanone causes an increase in the yield. This may be attributed to

the increase in electron density on the oxygen ofcarbonyl group, due to electron How Irom

-OCH3 group. This increased electron density accelerates the process of 1.2-addiiion of

NH^NHj.HCl which results in the ibrmation of an intermediate adduct. This then loses the

molecule of water to give hydrazone which undergoes cycli/alion and rearrangemeni to

give pyrazoline (5b).

V

OH

OH COPh ^ = ^ -OCH, ^

-HO

H

OCH Hc ^ -^C-C=CH/O>. COPh ^ - ^

NHNH

@0H QHCOPh o,^ 9 - C = C H / O \ O C H ,

N ^ ^ );JH H

/o? H C '

.OH

Of _ c = o il I x - ^

N . N > \ 0 > O C H ,

H (5b)

Experiment No. 15

Action of hydrazine hydrochloride on 3-benzoyl-2(2'-furyl)-6-methylchromanone (4c) :

Synthesis of3-(2-hydroxy-5-methylphenyl)-4-benzoyl-5-(2'-furyl)-A--pyraz

Reaction :

'OT Y^°l, NH,NH,HC1 H,C^C—^"^2 (

" ' ^ O ^ ^ ^ DMSO/Piperidine ^ ^ N ^ ^ O ^ H

(4c) (5c)

Properties and constitution of the compound (5c) :

The compound melted at 160" C.

The compound (5c) showed properties similar to those given in expi. No. I ^

Analytical results of the compound (5c) agreed with the molecular roniuila(\^H|^(),N,

Elemental analysis of the compound (5c) :

Analysis %C %H %N

Found 72.73 5.02 7.99

Calculated 72.83 5.20 8.09

Form the properties and analytical results, the compound (5e) was assigned the struc-

ture, 3-(2-hydroxy-5-methylphenyl)-4-benzoyl-5(2'-ruryl)---pyra/.oline.

t H

(5c)

107

Experiment No. 16

Action of hydrazine hydrochloride on 3-benzoylflavanone (4d):

Synthesis of3-(2-hydroxyphenyl)-4-benzoyl-5-phenyl-A^-pyrazoUne (5d):,

Mixture of 3-benzoylflavanone (4d) (0.01 mol, 3.28 g.) and hydrazine hydrochloride

(0.02 mol, 1.37 g) was refluxed in DMSO (15 ml) containing piperidine (0.5 ml) lor4-5 hr.

and processed as in Expt. No. 13. The product thus obtained was crystallised iVom eihanol

to get crystals of the compound (5d) m.p. 15 T'C, yield 67%.

Reaction :

NH.NH HCl " c ^ r . / " O -»

Q-

Mo) DMSO/Piperidine N^^. H

(4d) (5d)

Properties and constitution of the compound (5d):

The compound melted at 151" C.

The compound (5d) showed properties similar to those given in the Hxpi. No. 13.

Analytical results of the compound (5d) agreed with the moleculai" fomiula C„Hj^(),N,

Elemental analysis of the compound (5d) :

Analysis %C %H %N

Found 76.98 5.17 8.02

Calculated 77.19 5.26 8.19

108

Form the properties and analytical results, the compound (5d) was assigned the struc-

ture 3-(2-hydroxyphenyl)-4-benzoyl-5-phenyi-A--pyrazoline.

•or # H

(5d)

Experiment No. 17

Action of hydrazine hydrochloride on 3-benzoyl-4'-methoxyflavanone (4e):

Synthesis of3'(2-hydroxyphenyl)-4-benzoyl-5-(4'methoxyphenyl)-A^-pyraz.oline (Se) :

Mixture of 3-benzoyl-4'-methoxynavanone (4e) (0.01 mol, 3.5Hg) and hydrazine hy-

drochloride (0.02 mol, 1.37 g) was retluxed in DMSO (15 ml) containing piperidine (0.5

ml) for 4-5 hr. and processed as in Expt. No. 13. The product thus obatined was crystallised

from ethanol to get crystals of the compound (5e) ,m.p. 138", yield 85%.

Reaction:

NH.NH.HCl " w ^ c - ^^^^

,0H /o) OCH, O

' NH.NH.HCl K::^ DMSO/Piperidine N^^^-^Q/OCH,

H

(4e) (5e)

Properties and constitution of the compound (5e) :

The compound melted at 138"C.

The compound.(5e) showed properties similar to those given in Expt. No. 13

109

Analytical results of the compound (5e) agreed with the molecular formula C\,H,,(),N,

Elemental analysis of the compound (5e) :

Analysis %C %H %N

Found 74.05- 5.29 7.41

Calculated 74.19 5.38 7.53

From the properties and analytical results, the compound (5e) was assigned ihe suuc-

ture3(2-hydroxyphenyl)-4-benzoyl-5-anisyl-A--pyra/.oline.

@™ # \y^r—A

H

(5e)

Experiment No. 18

Action of hydrazine hydrochloride on 3-benzoyl-2-(2'-furyl)-chromanone (4f):

Synthesis of3-(2-hydroxyphenyl)-4-benzoyl-5-(2'furyl)-A^-pyrazoline (5f) :

Mixture of 3-benzoyl-2-(2'-furyl) chromanone (4i) (0.01 mol, 3.18 g) and hydrazine

hydrochloride (0.02 mol, 1.37 g) was refluxed in T^MSOcontaining piperidine (0.5 ml) lor

4-5 hr. and processed as in Expt. No. 13. The product thus obtained was crystallised Irom

ethanol to get crystals of the compound (5f) m.p. 160"C.. yield 65%.

Reaction :

no

.on /o^ NH,NH,.HC1 ^Q^r ^̂ "̂̂ ^ 1

DMSO/I^iperidine ^ - N ^ ^ O ' I

H (41) (51

Properties and constitution of the compound (5f) :

The compound melted at 16(fC.

The compound (51) showed properties similar to those given in Hxpi. No. 17

Analytical results of the compound (51) agreed with the molecular lornuila C, H|^(),N,

Elemental analysis of the compound (5f) :

Analysis %C %H %N

Found 72.21 4.76 S.3()

Calculated 72.28 4.82 8.43

From the properties and analytical results, the compound (51) was assigned the struc-

ture 3-(2-hydroxyphenyl)-4-benzoyl-5-(2'-luryl)---pyrazoline.

or # N

H

(51)

J

111

Section B

ii) Synthesis of I-carboxamido-3-(2-hydroxyphenyl)-4-aroyl-5-aryl-A^-pyrazoline (6a-f)

The most usual synthesis of pyrazolines is by the action of hydrazine or subsliluled

hydrazine on 2'-hydroxy-chalcones or Havanoiies. The formation of l-carboxamido-A--

pyrazolines from epoxyketones and semicarbazide has been reported by I'̂ l Hashash^'. SaraP'

prepared 5-phenyl-3-(2-methyl-4-oxo-4H-l-benz.opyran-3-yl)-A--pyrazoline-l-carboxamides

from 3-cinnamoyl-2-methylchromone and semicarbazide hydrochloride in ethanol contain-

ing little acetic acid. Thakare" synthesised l-carbOxamido-3-(2-hydroxyphenyi)-5-aryl-A--

pyrazolines by the reaction between 2'-hydroxychalconcs and semicarbazide hydrochloride

in ethanol. Recently Kedar**̂ also reported the synthesis of l-carboxamido-3,5-diaryl-A--

pyrazolines and l-carboxamido-3,5-diai7l-4-aix)yl-A--pyrazolines from 2'-hydroxychalcones

and 3-aroylflavanones by reaction with semicarbazide in alkaline ethanol containing little

piperidine respectively.

This section describes the synthesis of six variedly substituted l-carboxamido-3-(2-

hydroxyphenyl)-4-aroyl-5-aryl-A--pyrazolines (6a-f) from 3-aroyinavavnones (4a-f) and

semicarbazide hydrochloride in ethanolic KOH.

Experiment No. 19

Action of semicarbazide hydrochloride on 3-benzoyl-6-methylflavanone (4a) in ethanol:

Synthesis of I-carboxamido-3-(2-hydroxy-5-methylphenyl)-4-benzoyl-5-phenyl-A^-

pyrazoline (7a) :

A mixture of 3-benzoyl-6-methylflavanone (4a) (O.Ol mol, 3.42 g) and semicarbazide

hydrochloride (0.015 mol, 1.68 g) and aqueous KOH (1.5 mol, 0.42 g in 5ml water) was

retluxed in ethanol (15 ml) for three hours. The cooled reaction mixture was diluted with ice

112

cold water and acidified by 1:1 HCl. The semisolid thus obalined was iriluraled with elhanol

and crystallised from elhanol to get compound (6a) m. p. 171" C, yield 6{)'/i.

Reaction :

Y\2/ NH NHCONH. IPir^ /=" H r - (;•

CONH

(4a) (6a)

Detailed examination of the compound (6a) :

1. TLC studies indicated Rf value = 0.71 in CCK as solvent. 4

2. The compound (6a) is a white crystalline solid, m. p. I7I"C.

3. It gave deep green colouration with ethanolic I'cCl, indicating the presence ol Tree

phenolic OH group.

4. It gave deep blue colouration with concentrated H^SO^ showing the absence ol

-C-CH=CH- linkage.

5. It remained unchanged on boiling in acetic acid.

6. The analytical results of the compound (6a) agreed with the molecular lormula

asC,,H3,0,N3. .

7. Elemental analysis of the compound (6a)

Analysis %C %H %N

Found 72.02 5.17 10.61

Calculated 72.18 5.26 1()..52

113

8. From the elemental analysis and chemical properties the compound (6a) was lound lo he

l-carboxamido-3-(2-hydroXy-5-melhylphenyl)-4-ben/,oyl-5-phenyl-A--pyra/uline.

CONH,

(6a)

The proposed structure is futher confumed on the basis of following facts.

Reaction or3-benzoyl-6-melhyinavanone with semicarba/idc hydrociiloride may lead

to the formation of various products (A-D) shown below.

CONH, CONH,

(A) • (B)

.OH ,0H /o)

W < 0 / CONH,

(C) (D)

a) That (6a) is not semicarbozone of 3-ben/.oyl-6-methyinavanone (A) is ruled out on

114

the basis of the fact that (6a) remain unchanged on prolonged relluxing in acetic acid or

pyridine. Had (6a) been semicarba/one it would have changed U) l-carboxaniido-3-(2-

hydroxy-5-methylphenyl)-4-benzoyl-5-phenyl-A--pyra/.oline. This is also supported by

PMR of (6) (Spectrum No. 15) Which showed the presence of ABX paliern.

b) That (6a) is not semicarbazino-semicarba/.one of 3-ben/.oyl-6-melhyinavanone (H) is

ruled out on the basis of elemental analysis. Compound H required N. \l.lT/

Mechanism of the Reaction :

The mechanism of the reaction involves the nucleophilic attacl

cydization and rearrangement to give finally I-carboxaniido-3-(2-hydr()xy-5-meihylphenyl)-

4-benzoyl-5-phenylpyra/.oline.

HC

NHNHCONR

EtOH OH ^-^

H,C o H =0

V -

toNH,

= CH

A mixture of 3-benzoyl-4'-methoxy-6-niclhyinavanone (4b) (0.01 mol. 172 g) and

semicarbazide hydrochloride (0.015 mol, 1.68 g ) and aqueous KOH (I..5 mol. 0.42 g in 5

ml water ) was refluxed in ethanol (15 ml) for ̂ hours. The product was worked up as ui

experiment No. 19 and crystallised from ethanol to get the compound (6h) , m.p. i63"C',

yield 75% .

Reaction :

H

a) The IR spectrum of the compound (6b) (Specirum No. 13

showed the following main absorption hands'*'"'*''.

Reglon(cm')

37()()-3{)()()

3400-3000

1700-1600

. 1600-1450

Frequency

3400

3280-3220

1670

1590

Intensity

(w,b)

(w,h)

(s)

(s)

Correlation

O-H stretching

CO-NH, stretching

C=() stretching of

aroyl group

C=N stretching of

pyra/.oline

b) The UV-VIS spectrum of the compound (6b) (vSpectaim No. 14) recorded in C'HC1̂ showed

A.max at 268 which indicates carbonyl function.

c) The PMR spectrum of the compound (6h) (Spectrum No. 15) showed the important

absorption peak as follows*''* "'̂ ".

Chemical Shifts

in 5

2.1

3.75

5.1

5.9

6.82

6.98

7.26-7.82

Nature of

peak

(s)

(s)

(d)

(d)

(d)

'(d)

(m)

No. of Type of pnjtons

protons

3H

3H

IH

IH

IH ~

IH

lOH -

ArCH,

ArOCH,

H„

H.

— Ar-H

19

m

o z E P h> u o a

CO

1 r 1 r T 1 1 r -I r e c a a

t

. 1 ; in

J I I L

AvQOOQ 3u;'. • : .M iv ! ^ - . ; i n : II' mivour.in.lO? ivunii^ix

On the basis of elemental analysis chemical properlies and spectral resulis. the com-

pound (6b) was assigned the structure as l-caihoxamido-3-(2-hydroxy-5-melhylphenyl)-4-

benzoyl-5-(4-melhoxyphenyl)-A--pyra/.oline.

o OH

c-

Xo> c=o

H,C - \, ^'lvN>^(0)^0CH,

CONH,

(6b)

Experiment No. 21

Action of semicarbazide hydrochloride on 3-benzoyl-2-(2'-furyl)-6-methylchromanone

(4c):

Synthesis of l-carboxamido-3-(2-hydroxy-5-methylphenyl)-4-benzoyl-5-(2 'furyl)A^-

pyrazoline (6c) :

A mixture or3-ben7.oyl-2-(2'-furyl)-6-melhylchromanone (4e) (0.01 mol. 3.32 g) and

semicarbazide hydrochloride (0.015 mol. 1.68 g) aqueous KOH (1..^ mol. 0.42 g in 5 ml

water) was reiluxed in ethanol (\5 ml) for three hours. The product was worked up as m

Expt. No. 19 and crystallised from ethant)l to gel the compound (6c) m.p. 150" ('.

yield 60 %.

Reaction :

\ ^

OH / O

QJ J^O^ NHjNHCONH, / " ^ ^ C / "^^

^^O) aOH ^ ^^ Kf"^ CONH,

" ' ^ O

(*-0

120

Detailed examination of the product (6c):

The compound (6c) m.p. 15()"C gave deep green colouration with elhanolic leC'l,

solution. The other properties were identical with those described in lixperimenial No. 19

F">om the analytical results, the molecular formula of the compound (6c) was found to

beQ^H.p^N,.

Elemental analysis of the compound (6c):

Analysis %C %H %N

Found 67.81 4.80 11.00

Calculated 67.86 4.88 10.79

l-rom the analytical results, properties and by analogy with the compound (6a). the

compound (6c) was assigned the structure l-carboxamido-.'^-(2-hydroxy-5-meihylphenyl)-

4-benzoyl-5-(2'-furyI)-A--pyrazoline.

or # HX ' "S

CONH,

(6c)

Experiment No. 22

Action of semicarbazide hydrochloride on 3-benzoylflavanone (4d):

Synthesis of l-carboxamido-3-(2-hydroxyphenyl)-4-benzoyl-5-phenyl-A^-pyrazotine

(6d):

121

A mixture of 3-benzoylflavanone (4d) (0.01 mol. 3.28 g) and semicaiha/ide hydro-

chloride (0.015 mol, 1.68 g) and aqueous KOH (1.5 mol, 0.42 g in 5 ml water) wa.s relluxed

in ethanol (15 ml) for three hours, the product was worked up as in Hxpt. No. 19 and crys-

tallised from ethanol to get the compound (6d) m.p. 15()"C, yield 60%.

Reaction :

O f ° Y ^ NH^NHCONH, l^c^^^°"

f \,on ' I^MQ) CONH,

(4d) (6d)

Detailed examination of the product (6d) :

The compound (6d) m.p. 150"C gave green colouration with ethanolic leCi, .solution.

The other properties were identical with those described in lixpriment No. 19

From the analytical results, the molecular formula of the compound was found U) he

Elemental analysis of the compound (6d):

Analysis %C %H %N

Found 71.60 5.00 11.02

Calculated 71.69 4.93 10.91

From the analytical results, properties and by analogy with the compound (6a). the

122

compound (6d) was assigned the siruclurc l-cart)oxamido-3-(2-hydn)xyphenyl)-4-hen/oyl-

5-phenyl---pyrazoline.

/o) .OH o r ĉ ô CONH,

(6d)

Experiment No. 23

Action of semicarbazide hydrochloride on 3-benzoyl-4'-methoxyflavanone (4e) :

Synthesis of J-carboxamido-3'(2-hydroxyphenyl)-4-benzoyl-5-(4-methoxyphenyl)A'-

pyrazoline (6e) :

A mixture of 3-benzoyl-4'-methoxynavanone (4e) (0.01 mol, 3.58 g) and .semicarbazide

hydrochloride (0.015 mol. 1.68 g) and aqueous*KOH (1.5 mol. 0.42 g in 5 ml water) was

refluxed in ethanol (15 ml) for three hours, the product was worked up as in experiment No.

19 and crystallised from ethanol to get the compound (6e) m.p.. 142" C, yield 707r.

Reaction

OCH, NH,NHC()NH,

EtOH

OH

c. C=

N . N > < g > - O C H ,

CONH, (4e) (6e)

Detailed examination of the product (6e):

The compound (6e) m.p. 142" C gave deep green colouration wiili eihanolic leC'l

solution. The other properties were identical with tho.se described in experimeni No. 19

23

http://tho.se

From the analytical results, the molecular formula of the compound (6c) was found lo

.heq^H^.O^N,.

Elemental analysis of the compound (6e)

Analysis %C %H %N

Found 69.46 4.95 10.30

Calculated 69.39 5.06 10.12

From the analytical resuHs, properties and by analogy with the compound (6a). ihc

compound (6e) was assigned the structure l-carboxamido-3-(2-hydroxyphenyl-4-ben/oyl-

5-(4-methoxyphenyl)-A--pyrazoline.

ÔH / O ,

^nMoy OCH, CONH,

(61)

Experiment No. 24

Action of semicarbazide hydrochloride on 3-benzoyl-2-(2'furyl)-chromanone (4f):

Synthesis of l-carboxamido-3-(2-hydroxyphenyl)-4-benzoyl-(2'-furyl)-A^-pyrazoline

(6f):

A mixture of 3-ben/.oyl-2-(2'-furyl) chromanone (4f) (0.01 mol. 3. IX g) and

semicarbazide hydrochloride (0.015 mol. 1.68 g ) and aqueous KOH (1.5 mol. 0.42 g m 5

ml water) was refluxed in elhanol (15 ml) for three hours, the product was worked up as in

124

Experiment No. 19 and crystallised from ethanol to get the compound (61), m.p. 151-152"C,

yield 55%.

Reaction :

\U or ^ u j • c=o

CONH,

(40 (50

Detailed examination of the product (6f) :

The compound (60, m.p. 151-152°C gave deep green colouration with ethanolic leCl,

solution. The other properties were identical with those described in Experiment No. 19

From the analytical results, the molecular formula of the compound was Ibund to he

23 19 4 3'

Elemental analysis of the compound (6f)

Analysis %C %H %N

Found 67.02 4.47 11.32

Calculated 67.19 4.53 11.19

From the analytical results, properties and by analogy with the compound 6a. the

125

compound (60 was assigned the slruclure l-carboxamido-3-(2-hydroxyphenyl)-4-bcn/.oyl

5-(2'-furyl)---pyrazoline.

(of" c# STJi

CONH,

(61)

126

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